Alkyl or alkoxy substituted S-heterocyclic retinoids

ABSTRACT

Compounds of the formula    &lt;IMAGE&gt;  I  in which X is -S-, -SO- or -SO2-; R1 is C7-10-alkyl or C7-10-alkoxy; R2 is a residue of the formula   &lt;IMAGE&gt;   R3 is carboxy or lower-alkoxycarbonyl; and n is an integer of 1, 2 or 3; and salts of carboxylic acids of formula I can be used for the treatment of autoimmune diseases and diseases having a strong immunological component, such as psoriasis.

This is a division, of application Ser. No. 08/057,949 filed May 5,1993, now U.S. Pat. No. 5,391,766.

SUMMARY OF THE INVENTION

The present invention is concerned with novel alkyl or alkoxysubstituted S-heterocyclic compounds of the formula: ##STR3## in which Xis --S--, --SO-- or --SO₂ --; R¹ is C₇₋₁₀ -alkyl or C₇₋₁₀ -alkoxy;

R² is a residue of the formula ##STR4## R³ represents carboxy orlower-alkoxycarbonyl; and n is an integer from 1 to 3; as well as saltsthereof where R³ is carboxy.

The invention is also concerned with pharmaceutical preparations basedon the compounds of formula I or their salts and with a process for themanufacture of the compounds I.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower" used herein denotes groups with up to 6 carbon atoms.Preferred lower groups contain 1-4 carbon atoms, such as, for example,methyl, ethyl, isopropyl or 2-methylpropyl.

The terms C₇₋₁₀ -alkyl and C₇₋₁₀ -alkoxy denote alkyl and alkoxy groupswith 7-10 carbon atoms, such as heptyl, octyl, nonyl and decyl.

A preferred group of compounds of formula I comprises those in which R¹is heptyl, octyl, heptyloxy or octyloxy; R³ is carboxyl and X=SO₂.

The compounds of formula I can be obtained by

a) reacting a compound of the formula ##STR5## with a compound of theformula ##STR6## wherein R is lower-alkyl and either A is atriphenylphosphoniumethy-ethyl group ##STR7## or dialkoxyphosphinylethylgroup ##STR8## and B is formyl; or A is acetyl and B is atriphenylmethylphosphonium group --CH₂₋ P Q!₃ ³⁰ Y⁻ or adialkoxyphosphinylmethyl group --CH₂ --PO(OR)₂ ; and Q is phenyl; or by

b) reacting a compound of the formula ##STR9## with a compound of theformula ##STR10## wherein either A' is a triphenylmethylphosphoniumgroup --CH₂ --P Q!₃ Y³¹ or a dialkoxyphosphinylmethyl group --CH₂--PO(OR)₂ and B' is formyl; or A' is formyl and B is atriphenylmethylphosphonium group --CH₂ --P³⁰ Q!₃ Y³¹ or adialkoxyphosphinylmethyl group --CH₂ PO(OR₂) and n, Q and R have thesignificance given above, to give a compound of formula I in which R³ is--COOR and, if desired, saponifying the ester group --COOR and isolatingthe carboxylic acid obtained as such or as a salt; and/or oxidizing acompound of formula I obtained in which X is --S-- to a compound offormula I in which X is --SO-- or --SO₂ --.

The reaction of the compound II with the compounds III or IV and thereaction of the compound V with the compound VI can be carried outaccording to methods which are known per se for the Wittig or Hornerreaction.

The reaction of compounds having triphenylphosphonium groups (Wittigreaction) can be effected in the presence of an acid-binding agent, e.g.a strong base such as e.g. butyllithium, sodium hydride or the sodiumsalt of dimethyl sulphoxide, but primarily in the presence of anethylene oxide which is optionally substituted by lower alkyl, such as1,2-butylene oxide, optionally in a solvent, e.g. in an ether such asdiethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such asbenzene, in a temperature range lying between room temperature and theboiling point of the reaction mixture.

Examples of anions Y⁻ in the Wittig reagent are CI⁻, Br⁻, HSO₄ - andtosylate.

The reaction of compounds having dialkoxyphosphinyl groups (Hornerreaction) can be carried out in the presence of a base and, preferably,in the presence of an inert organic solvent, e.g. in the presence ofsodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran,dioxan or a 1,2-dimethoxyalkane, or also a sodium alcoholate in analkanol, e.g. sodium methylate in methanol, in a temperature rangebetween 0° and the boiling point of the reaction mixture.

A thus-obtained carboxylic acid ester of formula I can be hydrolyzed ina manner known per se, e.g. by treatment with alkalis, especially bytreatment with aqueous-alcoholic sodium or potassium hydroxide solutionin a temperature range lying between room temperature and the boilingpoint of the reaction mixture.

The thus-obtained carboxylic acid of formula I can be isolated in amanner known per se as such or as a salt, e.g. as an alkali salt,especially as the Na or K salt.

A compound of formula I in which X stands for --S-- can be oxidizedusing methods known per se to a compound of formula I in which X standsfor --SO³¹ or --SO₂ ³¹ . The oxidation can be carried out usingoxidation agents such as periodates, e.g. NaIO₄, or using organicperacids such as m-chloroperbenzoic acid. About one equivalent ofperacid is used in the oxidation using organic peracids in order toobtain a sulphoxide compound (X=SO), whereas the use of two equivalentsof peracid leads to sulphones (X=SO₂).

The compounds of formula I can be present as double bond isomers. Theygenerally occur in the trans or all-trans form in the process. Cisisomers which may occur can be isolated from the mixture in a mannerknown per se where required.

The starting materials of formulae II-VI are known or can be prepared inanalogy to the known compounds or according to methods described in thefollowing Examples.

The preferred compounds of this invention have the following formulas:##STR11## wherein R¹, R², R³ and X are as above

Among the preferred compounds of formula I-D are those compounds whereR² is ##STR12## and R³ is as above; as well as those compounds offormula I-D where X is --SO₂ -- and R² is R-E. Also preferred as thosecompounds or formula I-C wherein X is SO₂.

The compounds of formula I are retinoic acid α-receptor (RARα-receptor)inhibitors. It has been found that the compounds of formula I suppressretinoid-induced malformations. The compounds of formula I can thereforebe used for the prevention of teratogenic effects which can occur duringthe therapeutic use of retinoids.

Furthermore, the compounds of formula I can be used for the treatmentand prevention of disease states which can be caused by anover-regulation of the RARα-receptor. Among these diseases areautoimmune diseases or other disorders having a strong immunologicalcomponent such as e.g. psoriasis or other dermatological conditions.

Also included-in this invention are salts of these compounds of formulaI wherein R³ is carboxyl above with pharmaceutically acceptable,non-toxic, inorganic or organic bases, e.g., alkali metal and alkalineearth metal salts. Among the preferred salts are the sodium, potassium,magnesium or calcium salts, as well as salts with ammonia or suitablenon-toxic amines, such as lower alkyl amines, for example triethylamine,hydroxy-lower alkylamines, for example 2-hydroxyethylamine,bis-(1-hydroxyethyl)amine or tris(2-hydroxyethyl)-amine,cycloalkylamines, for example dicyclohexylamine, or benzylamines, forexample N,N'-dibenzylethylenediamine, and dibenzylamine. These salts canbe prepared by treating the compounds of formulae I and II, where R₉ ishydrogen with inorganic or organic bases by conventional means wellknown in the art.

In view of their activity, the compounds of formula i as well as saltsthereof are effective as disease modifiers for treating rheumatoidarthritis as well as related disorders such as osteoarthritis. Thecompounds of formula I and II also have activity as immunosuppressants.

The compounds of formula I and salts thereof can be utilized to treatpatients suffering from rheumatoid arthritis and related disorders. Insuch cases, the compounds modify the effects of these diseases byreducing destruction of the bone joints caused by this disease as wellas reducing inflammation, heat and pain of the bone joints which resultsfrom rheumatoid arthritis and related disorders. The compounds offormula and salts thereof are also useful for treating diseasesresulting from immune hyperactivity such as transplantationautoimmunity, autoimmune disease and graft versus host disease. Theunexpected lack of toxicity of the compounds of this invention increasestheir ability in treating these diseases.

The compounds of formula I and their salts can be used in the form ofpharmaceutical preparations.

The preparations for systemic use can be produced e.g. by adding acompound of formula I or a salt thereof as the active ingredient tonon-toxic inert solid or liquid carriers which are usual in suchpreparations.

The preparations can be administered enterally, parenterally ortopically. Preparations in the form of tablets, capsules, dragees,syrups, suspensions, solutions and suppositories are e.g. suitable forenteral administration.

Preparations in the form of infusion or injections solutions aresuitable for parenteral administration.

For enteral and parenteral administration the compounds of formula I canbe administered to adults in amounts of about 1-100 mg, preferably 5-30mg/day.

For topical use the active substances are conveniently used in the formof salves, tinctures, creams, solutions, lotions, sprays, suspensionsand the like. Salves and creams as well as solutions are preferred.These preparations designed for topical use can be produced by mixingthe active ingredients with non-toxic, inert solid or liquid carrierswhich are suitable for topical treatment and which are usual in suchpreparations.

For topical use there are conveniently suitable about 0.1-5%, preferably0.3-2%, solutions as well as about 0.1-5%, preferably 0.3-2%, salves orcreams.

If desired, an antioxidant, e.g. tocopherol, N-methyl-γ-tocopheramine aswell as butylated hydroxyanisole or butylated hydroxytoluene, can beadmixed with the preparations.

The following abbreviations are used in the Examples which follow andwhich illustrate the present invention in more detail:

    ______________________________________    DMF              dimethylformamide    DMSO             dimethyl sulphoxide    THF              tetrahydrofuran    RT               room temperature    m.p.             melting point    i.v.             in a vacuum    EtOEt            diethyl ether    tBuOH            tert.-butanol    AcOEt            ethyl acetate    ______________________________________

EXAMPLE 1

a) 14.9 g of NaH, 50% in paraffin oil, were washed twice with pentane,dried in a water-jet vacuum and suspended in 60 ml of DMF. A solution of64.8 g of 3-heptyloxyphenol in 320 ml of DMF was added dropwise theretowhile cooling with ice. After stirring at 0° C. for 45 minutes asolution of 42.3 g of dimethyl-thiocarbamoyl chloride in 100 ml of DMFwas slowly added dropwise to this reaction mixture and the mixtureobtained was stirred at room temperature overnight. Thereafter, it waspoured on to ice-water, acidified with 6N hydrochloric acid andextracted with AcOEt. The organic phase was washed with water, saturatedNaHCO₃ solution and H₂ O, dried over sodium sulphate and evaporated.After filtration of the crude product over a silica gel column (eluenthexane/AcOEt=4:1) there were obtained 86.7 g ofO-(3-heptyloxyphenyl)dimethylthiocarbamate as a pale yellow oil.

b) 80 g of O-(3-heptyloxyphenyl)dimethylthiocarbamate in 20 g portionswere heated to 260° C. for 8 hours in a metal bath. The thus-obtainedS-(3-heptyloxyphenyl)dimethylthiocarbamate was used in the next stepwithout further purification.

c) 10 g of LiAlH₄ were suspended in 200 ml of THF and treated dropwiseat 0° C. with a solution of 77 g ofS-(3-heptyloxyphenyl)dimethylthiocarbamate in 200 ml of THF. Afterstirring at room temperature for 1 hour a solution of 46.5 g of3,3-dimethylallyl bromide in 200 ml of THF was added dropwise theretoand the mixture was stirred for a further 45 minutes. The reactionmixture was subsequently poured into an ice-water/6N hydrochloric acidmixture and extracted with EtOEt. After washing, drying and evaporationthere was obtained a dark oily crude product which, after filtrationover a silica gel column (eluent hexane/AcOEt=9:1), gave 64 g of heptylm- (3-methyl-2-butenyl)thio!phenyl ether as a yellow oil.

d) 76.9 g of heptyl m- (3-methyl-2-butenyl)thio!phenyl ether weredissolved in 1.5 I of toluene, treated with 55 g of p-toluenesulphonicacid and heated on a water separator for 20 hours. The cooled reactionmixture was diluted with AcOEt, washed twice with dilute sodiumbicarbonate solution and water, dried and evaporated. There was obtaineda yellow oil which consisted of 3 parts of7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran and of 1 partof 5-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran. Columnchromatography (silica gel, eluent hexane/1% AcOEt) gave 48.6 g of pure7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran as a paleyellow oil.

e) 4.8 ml of acetyl chloride were dissolved in 80 ml of methylenechloride and treated portionwise at 0° C. with 9.1 g of aluminiumchloride. After stirring at 0° C. for 30 minutes a solution of 20.7 g of7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran in 70 ml ofmethylene chloride was added dropwise thereto, the mixture was stirredat 0° C. for 2 hours, poured on to ice-water and extracted with ether.After washing with water, drying and evaporation the crude product wasrecrystallized from hexane and there were obtained 15.5 g of6-acetyl-7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran incolourless crystals, m.p. 69°-71° C.

f) 14 g of6-acetyl-7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran weredissolved in 200 ml of chloroform and treated dropwise at 0° C. with asolution of 8.5 g of m-chloroperbenzoic acid (85%) in 120 ml ofchloroform. After stirring at 0° C. for 2 hours a further 8.5 g ofm-chloroperbenzoic acid in 120 ml of chloroform were added dropwise. Thereaction mixture was stirred at 0° C. overnight, poured intoice-water/dilute sodium chloride solution and extracted with methylenechloride. The organic phase was washed twice with water, dried andevaporated. After filtration of the crude product over a silica gelcolumn (eluent hexane/AcOEt=4:1) and recrystallization from AcOEt therewere obtained 12.5 g of7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl methylketone 1,1-dioxide in colourless crystals, m.p. 92°-93° C.

g) 3 g of sodium hydride (50% in mineral oil) were washed twice withpentane, dried in a water-jet vacuum and suspended in 50 ml of abs.DMSO. A solution of 19.3 g of diethyl (4-carbethoxybenzyl)phosphonate in100 ml of abs. DMSO was slowly added dropwise thereto at roomtemperature. After stirring at room temperature for 2 hours the mixturewas treated dropwise with a solution of 10.5 g of7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl methylketone 1,1-dioxide in 50 ml of abs. DMSO and the mixture obtained wasstirred at 40° C. for a further 2 hours. After cooling the reactionmixture was poured on to ice-water, acidified with 2N hydrochloric acidand extracted with ethyl acetate. The organic phase was washed withwater, dried over sodium sulphate and evaporated. The oily dark orangeresidue was filtered over a silica gel column (eluent hexane/AcOEt=2:1)and gave 13.5 g of ethyl p- (E,Z)-2-3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)-2'H-1-benzothiopyran-6'-yl!propenyl!benzoate1',1'-dioxide as a yellow oil (E/Z ratio about 1:1).

EXAMPLE 2

13.5 g of ethyl p- (E,Z)-2-3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)-2'H-1-benzothiopyran-6'-yl!propenyl!benzoate1',1'-dioxide were dissolved in 250 ml of ethanol and treated with asolution of 14.6 g of potassium hydroxide in 100 ml of water. Afterstirring at 50° C. for 3 hours the reaction mixture was poured on toice-water, acidified with 3N hydrochloric acid and extracted with AcOEt.The organic phase was washed with water, dried and evaporated. Theresidue was recrystallized from ethyl acetate/hexane and gave 10.2 g ofan E/Z mixture of the corresponding acids. By preparative HPLC (reversephase, eluent hexane/THF=9:1+0.1% acetic acid) there were obtained,after recrystallization from AcOEt/hexane, 4.1 g of p- (E)-2-3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)!-2'H-1-benzothiopyran-6'-yl!benzoic acid 1',1'-dioxide incolourless crystals, m.p. 168°-169° C., as well as 5.2 g of p- (Z)-2-3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)-2'H-1-benzothiopyran-6'-yl!propenyl!-benzoicacid 1',1'-dioxide, m.p. 176°-178° C.

The Z compound can be converted by irradiation in THF with a Hg highpressure lamp into a 1:1 mixture of the E/Z isomers from which furtherpure E compound can be obtained by preparative HPLC.

EXAMPLE 3

a) 13.6 g of6-acetyl-7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran weredissolved in 270 mi of THF. 164 ml of a 1 molar solution ofvinylmagnesium bromide in THF were added dropwise thereto at -15° C. andthe mixture was stirred at room temperature overnight. The reactionmixture was subsequently poured into ice-cold saturated ammoniumchloride solution, extracted with EtOEt, washed with water, dried andevaporated. There was obtained a yellow-brown oil which was immediatelydissolved in 270 ml of acetonitrile and treated portionwise whilestirring with 16.3 g of triphenylphosphine hydrobromide. After stirringthe reaction mixture at 50° C. for 2.5 hours it was evaporated and theresidue was dissolved in 500 ml of ethanol (80%) and extractedrepeatedly with hexane. The ethanolic solution was evaporated and theresidue was dissolved in methylene chloride. After drying over sodiumsulphate the solution was again evaporated and the foam-like residue wasstirred with hexane for several hours, the crystalline precipitate whichformed in the meanwhile was filtered off, washed with hexane and driedat 50° C. in a high vacuum. There were obtained 26.6 g of 3-(E)-(7-heptyloxy-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-2-butenyl!triphenylphosphoniumbromide, m.p. 88° C. (decomposition).

b) 25 g of the phosphonium salt obtained in a) were dissolved in 250 mlof THF and treated dropwise at -20° C. with 25 ml of butyllithium, 1.6molar in hexane. After 15 minutes a solution of 6.3 g of ethyl(E)-3-formyl-crotonate in 30 ml of THF was added dropwise to thered-brown reaction mixture and the mixture obtained was stirred at roomtemperature for a further 45 minutes. It was then poured into 500 ml ofa methanol/water mixture (6:4), extracted repeatedly with hexane, thenon-aqueous phase was washed 3 times with water, dried and evaporated.The yellow oily residue was dissolved in 500 ml of acetonitrile and,after the addition of 560 mg of triphenylphosphine, treated with 28 mlof 0.125% solution of palladium(II) nitrate in acetonitrile. The mixturewas heated to 50° C. for 5 hours, subsequently evaporated and the crudeproduct was filtered over a short silica gel column (eluent hexane/1%AcOEt). There were obtained 13.7 g of a yellow oil which consisted of amixture of the corresponding (4Z, 6Z), (all-E) and (6Z) compound. Thefurther separation was effected by medium pressure chromatography usingLobar finished columns (Merck) (eluent hexane/3% AcOEt) and gave 6.6 gof ethyl (aII-E)-7-7-heptyloxy-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl!-3-methylocta-2,4,6-trienoateas a yellow oil.

EXAMPLE 4

500 mg of the (all-E) ethyl ester obtained in Example 3 were dissolvedin 20 ml of ethanol and treated with a solution of 560 mg of potassiumhydroxide in 10 ml of water. After 3 hours at 50° C. the clear yellowsolution was poured on to ice-water, acidified with cold 3N hydrochloricacid and extracted with AcOEt. After drying and evaporation the crudeproduct was recrystallized from AcOEt/hexane and there were obtained 150mg of (aII-E)-7-7-heptyloxy-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl!-3-methyl-2,4,6-octatrienoicacid as yellow crystals, m.p. 158°-160° C.

EXAMPLE 5

Oxidation of the (all-E) ethyl ester obtained in Example 3 with 1equivalent of m-chloroperbenzoic acid at 0° C. in chloroform as thesolvent gave ethyl (aII-E)-7-7-heptyloxy-1-oxo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl!-3-methyl-octa-2,4,6-trienoateas a yellow oil which was converted by hydrolysis in analogy to Example4 into (aII-E)-7-7-heptyloxy-1-oxo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl!-3-methyl-octa-2,4,6-trienoicacid. Melting point 195°-197° C. (from AcOEt/hexane).

EXAMPLE 6

Oxidation of the (all-E) ethyl ester obtained according to Example 3with 2.2 equivalents of m-chloroperbenzoic acid at 0° C. in chloroformgave, after recrystallization from hexane, ethyl (all-E)-7-7'-(heptyloxy)-3',4'-dihydro-4',4'-dimethyl-2'H-1-benzothiopyran-6'-yl!-3-methyl-2,4,6-octatrienoate1',1'-dioxide, m.p. 105°-107° C. Hydrolysis of this compound in analogyto Example 4 gave, after recrystallization from AcOEt/hexane, (all-E)-7-7'-(heptyloxy)-3',4'-dihydro!-4',4'-dimethyl-2'H-1-benzothiopyran-6'-yl)-3-methyl-2,4,6-octatrienicacid 1',1'-dioxide, m.p. 140°-141° C.

EXAMPLE 7

a) A solution of 10 g of m-hydroxybenzaldehyde in 100 ml of DMF wasadded dropwise at 0° C. to a suspension of 4 g of sodium hydride (50% inmineral oil) in 50 ml of DMF. The mixture was stirred at 0° C. for afurther hour and subsequently a solution of 11.1 g ofdimethylthiocarbamoyl chloride in 150 ml of DMF was added dropwisethereto. The mixture was stirred at room temperature overnight, pouredon to ice-water, acidified with 6N hydrochloric acid and extracted withAcOEt. After drying the organic phase, evaporation and filtration of thecrude product over a silica gel column (eluent hexane/AcOEt=3:1) therewere obtained 10.2 g of O-(3-formylphenyl)dimethylthiocarbamate as ayellowish oil. This product was heated to 230° C. for 8 hours underargon in a metal bath and gave, after filtration over a silica gelcolumn (eluent hexane/AcOEt=4:1, then 1:1) and recrystallization fromEtOEt at -78° C., 7.3 g of S-(3-formylphenyl)dimethylthiocarbamate ingolden yellow crystals, m.p. 76°-77° C.

b) 13.2 g of n-heptyltriphenylphosphium bromide were suspended in 200 mlof THF and treated dropwise at -10° C. with 30 ml of n-butyllithium, 1.6molar in hexane. After stirring at 0° C. for 1 hour there was obtained aclear red solution to which a solution of 6 g ofS-(3-formylphenyl)dimethylthiocarbamate in 100 ml of THF was addeddropwise. The reaction mixture was stirred at room temperature for 2hours, poured into a methanol/water mixture (6:4) and extracted withhexane. The non-aqueous phase was washed repeatedly with water, driedand evaporated. After filtration over a silica gel column (eluenthexane/AcOEt=9:1) there were obtained 6.5 g ofS-(3-(1-octenylphenyl)dimethylthiocarbamate as a colourless oil (E/Zratio about 1:2). 3 g of this product were dissolved in 250 ml ofglacial acetic acid and, after the addition of 6 g of platinum/charcoal(5%), hydrogenated at 80° C./10 bar. After 1 hour the hydrogenation wasinterrupted, the catalyst was filtered off and the filtrate wasevaporated. After filtration over a silica gel column eluenthexane/AcOEt=9:1) there were obtained 2.4 g ofS-(3-octylphenyl)dimethylthiocarbamate as a colourless oil.

c) 0.4 g of lithium aluminium hydride was suspended in 25 ml of THF. Asolution of 2.4 g of S-(3-octylphenyl)dimethylthiocarbamate in 30 ml ofTHF was added dropwise thereto at 0° C. and the mixture was stirred at0° C. for 2 hours. Subsequently, a solution of 1.2 g of3,3-dimethylallyl bromide in 10 ml of THF was added dropwise thereto andthe mixture was stirred at 0° C. for a further 2 hours. The reactionmixture was poured on to ice-water, acidified with 6N hydrochloric acid,extracted with EtOEt, dried and evaporated. After filtration over asilica gel column (eluent hexane/AcOEt=4:1) there were obtained 2.3 g of3-octylphenyl (3-methyl-2-butenyl) thioether as a colourless oil. Thisproduct was dissolved in 100 ml of toluene and, after the addition of 2g of p-toluenesulphonic acid, heated to reflux for 20 hours on a waterseparator. After cooling the reaction mixture was neutralized by theaddition of aqueous sodium bicarbonate solution and extracted withAcOEt. After filtration over a silica gel column (eluenthexane/AcOEt=9:1) there were obtained 2.1 g of7-octyl-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran as a pale yellowishoil.

d) 0.6 g of acetyl chloride was dissolved in 50 ml of methylene chlorideand treated portionwise at 0° C. with 1 g of aluminium chloride. After15 minutes a solution of 2.1 g of7-octyl-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran in 50 ml ofmethylene chloride was added dropwise thereto. The mixture was stirredat 0° C. for 2 hours, poured on to ice-water and extracted withmethylene chloride. The crude product was purified by chromatography ona Lobar finished column (Merck) (eluent hexane/AcOEt 1%). There wereobtained 1.3 g of6-acetyl-7-octyl-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran as a paleyellowish oil.

e) 1.3 g of6-acetyl-7-octyl-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran weredissolved in 100 ml of chloroform. At 0° C. there were added dropwisethereto firstly 1 equivalent (0.74 g) of 85% m-chloroperbenzoic aciddissolved in 50 ml of chloroform and after 2 hours a further equivalentof m-chloroperbenzoic acid. The mixture was stirred at 0° C. overnight,poured on to ice-water/sodium carbonate and extracted with methylenechloride. After recrystallization of the crude product from AcOEt/hexanethere was obtained 1 g of6-acetyl-7-octyl-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-1,1-dioxidein colourless crystals, m.p. 77°-78° C.

f) In an analogy to Example 1 g), by reacting 0.95 g of6-acetyl-7-octyl-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-1,1-dioxide with 1.8 g of diethyl(4-carbethoxybenzyl)phosphonate, after deprotonization with sodiumhydride in dimethyl sulphoxide and flash chromatography of the crudeproduct on silica gel (hexane/AcOEt=1:1), there were isolated 1.3 g ofethyl 4-2-(4,4-dimethyl-7-octyl-1,1-dioxo-3,4-dihydro-2H-1-benzothiopyran-6-yl)-propenyl!-benzoateas a pale yellow oil with an E/Z ratio of about 4:9. The E/Z ratio canbe shifted in favour of the E isomer (E/Z ˜1:1) by irradiating the crudeproduct in THF with a Hg high pressure lamp for 5 hours. By preparativeHPLC (diisopropyl ether/hexane=55:45) of 0.9 g of E/Z mixture there wereobtained 300 mg of the E isomer and 430 mg of the Z isomer as paleyellowish oils.

EXAMPLE 8

300 mg of ethyl 4-2-(4,4-dimethyl-7-octyl-1,1-dioxo-3,4-dihydro-2H-1-benzothiopyran-6-yl)-propenyl!-benzoatewere dissolved in 30 ml of ethanol. After the addition of a solution of330 mg of potassium hydroxide in 10 ml of water the mixture was heatedto 40° C. for 3 hours. The clear reaction mixture was poured on toice-water, acidified with 3N hydrochloric acid and repeatedly extractedwith AcOEt. After recrystallization of the crude product fromAcOEt/hexane there were obtained 210 mg of (E)-4-2-(4,4-dimethyl-7-octyl-1,1-dioxo-3,4-dihydro-2H-1-benzothiopyran-6-yl)-propenyl!-benzoicacid in white crystals, m.p. 176°-178° C.

EXAMPLE 9

1.84 g of1-(1,1-dioxo-5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanolwere placed in 20 ml of acetonitrile and treated with 1.84 g oftriphenylphosphine hydrobromide. The mixture was heated under reflux for65 hours, cooled and evaporated i.v. The residue was taken up in CH₂Cl₂, dried over Na₂ SO₄ and again evaporated. Trituration in 100 ml ofEtOEt/hexane (1:1) finally yielded 2.82 g of phosphonium salt as whitecrystals which were reacted as follows:

The crystals are dissolved in 25 ml of abs. THF under argon anddeprotonized at 0° C. by the dropwise addition of 3.9 ml of 1.55M nBuLi(hexane). 814 mg of ethyl 4-formylbenzoate were added to the red ylidsolution after 15 minutes and the mixture was left to react at 0° C. for1 hour and at room temperature for 1 hour. Extraction with AcOEt,washing with water, drying, evaporation, flash chromatography on silicagel (hexane/AcOEt=85/15) and three-fold recrystallization fromhexane/AcOEt finally gave 702 mg of methyl (E)-4-2-(8-octyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoateas white crystals, m.p. 79°-80° C.

The1-(1,1-dioxo-5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanolused as the starting material can be prepared as follows:

a) 16.9 g of methoxymethyltriphenylphosphonium chloride were placed in100 ml of abs. THF and treated slowly at -5° C. under argon with 30 mlof 1.55M nBuLi. After 15 minutes a solution of 8.26 g of8-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-one in 50 ml of THF wasslowly added dropwise and the mixture was left to react for 2 hours.Then, the reaction mixture was partitioned between hexane andEtOH/water=8/2, the lighter phase was dried and evaporated i.v. Therewere obtained 9.1 g of crude enol ether mixture which was hydrolyzed in70 ml of THF under argon using 70 ml of 35% HClO₄. After 2 hours at roomtemperature the mixture was poured on to ice, washed with water, driedand evaporated. Flash chromatography on silica gel (hexane/AcOEt=95/5)gave 6.86 g of 8-bromo-2,3,4,5-tetrahydro-1-benzothiepine-5-carbaldehydeas a colourless oil (91.5% pure according to GC).

b) 6.86 g of the aldehyde obtained in a) were placed in 70 ml of abs.tBuOH under argon and treated with 5.76 g of K tert.-butylate. Themixture was cooled to about 15° C. internal temperature and 4.3 ml ofmethyl iodide were slowly added dropwise. The mixture was stirred for afurther 2 hours, poured on to ice, extracted with EtOEt, washed withwater and NaCl soln., dried and evaporated. Flash chromatography onsilica gel (hexane/AcOEt=96/4) yields 3.24 g of α-methylated aldehyde asa colourless oil.

c) This 3.24 g of8-bromo-5-methyl-2,3,4,5-tetrahydro-1-benzothiepine-5-carbaldehyde wereplaced in 45 ml of diethylene glycol and treated with 1.38 ml ofhydrazine hydrate and 3.23 g of KOH pellets. The mixture was heated,firstly to 100° C. for 1 hour and subsequently to 180° C. for 3 hours.After cooling the mixture was poured on to ice, extracted with EtOEt,washed with water, s dried and evaporated i.v. Flash chromatography onsilica gel (hexane) gave 2.58 g of8-bromo-5,5-dimethyl-2,3,4,5-tetrahydro-1-benzothiepine as colourlesscrystals, m.p. 81°-82° C.

d) 2.54 g of the above bromide were placed in 30 ml of abs. THF underargon and converted into the corresponding Li compound at -78° C. by thedropwise addition of 6.3 ml of 1.5M nBuLi. After 30 minutes 2.9 ml ofanhydrous nitrobenzene were added thereto at -78° C. After 1 hour themixture was poured on to ice, extracted with EtOEt, washed with water,dried and evaporated. Flash chromatography on silica gel (hexane/AcOEt,95:5) yielded 1.08 g of5,5-dimethyl-2,3,4,5-tetrahydro-1-benzothiepin-8-ol as a brownish oil.

e) 340 mg of NaH (about 50%) were placed in 10 ml of abs. DMF underargon. 1.08 g of 5,5-dimethyl-2,3,4,5-tetrahydro-1-benzothiepin-8-oldissolved in 10 ml of abs. DMF were added dropwise thereto at 0° C. andthe mixture was stirred for 30 minutes. Then, 1.36 g of 1-octyl bromidewere added and the mixture was left to react at room temperature for 2hours. The mixture was poured on to ice, extracted with EtOEt, washedwith water, dried and evaporated. Flash chromatography on silica gel(hexane/AcOEt=99/1) yielded 1.60 g of5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepine as acolourless oil.

f) 0.86 ml of AcCl and 1.24 g of AlCl₃ were placed in 17 ml of CH₂ Cl₂under argon. 1.60 g of5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepine dissolved in15 ml of CH₂ Cl₂ were added dropwise thereto at -20° C. After 15 minutesthe mixture was poured on to ice, extracted with EtOEt, washed withbicarbonate and NaCl solution, dried and evaporated. Flashchromatography on silica gel (hexane/AcOEt=95/5) yielded 1.97 g of1-(5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanoneas a colourless oil.

g) 1.93 g of1-(5,5-dimethyl-8-octyloxy-2,3,4,S-tetrahydro-1-benzothiepin-7-yl)-ethanonewere placed in 40 ml of CH₂ Cl₂ and treated at -25° C. with 3.81 g ofm-chloroperbenzoic acid (about 85%). The mixture was stirred at 0° C.for 2.5 hours, poured on to ice, extracted with AcOEt, washed insuccession with pyrosulphite soln., 2N NaOH, water and NaCl soln., driedand evaporated. Flash chromatography on silica gel (hexane/AcOEt=8/2)gave 1.77 g of 1-(1,1-dioxo- 5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanone as a colourless oil.

h) 1.77 g of1-(1,1-dioxo-5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanonewere dissolved in 15 ml of EtOH and treated with 1.68 mg of NaBH₄. After2 hours the mixture was poured on to ice, extracted with AcOEt, washedwith water, dried and evaporated. There were thus obtained 1.84 g of1-(1,1-dioxo-5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanolas a colourless oil which was uniform according to TLC.

EXAMPLE 10

In analogy to Example 9 there were manufactured:

Methyl (E)-4-2-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoateas white crystals, m.p. 107.5°-108.5° C.;

methyl (E)-4-2-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoateas white crystals, m.p. 92°-93° C.

EXAMPLE 11

193 mg of methyl (E)-4-2-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoatewere placed in 2 ml of THF/EtOH (1:1) and treated with 0.37 ml of 3NNaOH. The mixture was stirred at room temperature overnight, poured onto ice, extracted with AcOEt, washed with a small amount of water, driedand evaporated i.v. Crystallization from AcOEt yielded 152 mg of (E)-4-2-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoicacid as white crystals, m.p. 153°-154° C.

EXAMPLE 12

In analogy to Example 11 there were manufactured:

(E)-4- 2-(8-Hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoic acid aswhite crystals, m.p. 157°-158° C.; and

(E)-4-2-(8-octyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoicacid as white crystals, m.p. 168°-169° C.

EXAMPLE 13

3.58 g of1-(5,5-dimethyl-8-octyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanolwere placed in 20 ml of acetonitrile and treated with 3.34 g oftriphenylphosphine hydrobromide. The mixture was heated under reflux for70 hours, cooled and evaporated i.v. The residue was taken up in CH₂Cl₂, dried over Na₂ SO₄ and again evaporated. Trituration in 200 ml ofEtOEt/hexane (1:1) finally yielded 5.67 g of phosphonium salt as whitecrystals. This phosphonium salt was dissolved in 80 ml of abs. THF underargon and deprotenized at 0° C. by the dropwise addition of 7.45 ml of1.55M nBuLi. After 15 minutes 1.60 g of methyl 4-formylbenzoate wereadded thereto and the mixture was left to react at room temperature for1 hour. Extraction with AcOEt, washing with water, drying, evaporation,flash chromatography on silica gel (hexane/AcOEt=80/20) and two-foldrecrystallization from hexane/AcOEt finally gave 1.41 g of methyl (E)-4-2-(5,5-dimethyl-8-octyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoateas white crystals, m.p. 8520 -86° C.

The1-(5,5-dimethyl-8-octyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanolused as the starting material was prepared as follows:

a) The corresponding Grignard compound was prepared from 3.00 g of8-bromo-5,5-dimethyl-2,3,4,5-tetrahydro-1-benzothiepine and 340 mg of Mgshavings in 30 ml of abs. THF under argon. After cooling to -20° C.there were added thereto 220 mg of purified CuI followed by 3.18 ml of1-iodooctane. The mixture was warmed to 0° C. and, after 1.5 hours,poured into ice/NH₄ Cl solution. Extraction with EtOEt, washing withwater and NaCl solution, drying, evaporation and flash chromatography onsilica gel (hexane) yielded 2.56 g of5,5-dimethyl-8-octyl-2,3,4,5-tetrahydro-1-benzothiepine as a colourlessoil.

As described under Example 9f), g) and h), this5,5-dimethyl-8-octyl-2,3,4,5-tetrahydro-1-benzothiepine was acetylated,oxidized to the sulphone and finally reduced with NaBH₄ to1-(5,5-dimethyl-8-octyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanol.

EXAMPLE 14

In analogy to Example 11 there was manufactured:

(E)-4-2-(5,5-Dimethyl-8-octyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoicacid as white crystals, m.p. 164°-165° C.

EXAMPLE 15

a) 2.20 g of1-(5,5-dimethyl-8-hexyloxy-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanone,prepared in analogy to Example 9f), were placed in 20 ml of abs. THFunder argon and treated at -20° C. with 9.9 ml of 1M vinylmagnesiumbromide solution (THF). After completion of the addition (clearlyexothermic) the mixture was left to react for 1 hour and then poured onto ice/NH₄ Cl. Extraction with EtOEt, washing with saturated NaClsolution, drying and evaporation followed by flash chromatography onsilica gel (hexaneAcOEt=95/5) gave 2.16 g of tertiary alcohol as acolourless oil.

b) The foregoing alcohol was dissolved in 15 ml of acetonitrile andtreated with 2.45 g of triphenylphosphine hydrobromide. The mixture wasstirred at room temperature overnight, the solvent was removed i.v. andthe residue was taken up in CH₂ Cl₂. Drying, evaporation and digestionin 200 ml of EtOEt/hexane=1/1 yielded 4.14 g of rearranged phosphoniumsalt as a pink solid.

c) 4.14 g of the phosphonium salt were placed in 20 ml of 1,2-butyleneoxide and treated with 691 mg of ethyl (E)-3-formylcrotonate. Themixture was heated to reflux for 1 hour, cooled, poured on to ice andextracted with EtOEt. Washing with water and saturated NaCl solutiondrying, evaporation and flash chromatography on silica gel(hexane/AcOEt=96/4) yielded 2.58 g of triene ester which was isomerizedlargely to the all-trans compound as follows:

d) 2.58 g of the reiene ester were dissolved in 25 ml of acetonitrileunder argon and 37 mg of Pd(II) nitrate, 134 mg of triphenylphosphineand 35 microliters of triethylamine were added thereto. The mixture wasstirred at 50° C. for 4 hours and worked up. Renewed flashchromatography on silica gel (hexane AcOEt=96/4) yielded 2.33 g ofalmost isomer-pure ethyl(2E,4E,6E)-7-(8-hexyloxy-5,5-dimethyl-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate as a pale yellow oilwhich was oxidized to the sulphone as follows:

e) The ester was placed in 75 ml of CH₂ Cl₂ and the solution was treatedat -20° C. with 2.4 eq. of m-chloroperbenzoic acid. The mixture wasallowed to warm to 0° C. and the reaction was followed by thin-layerchromatography. After 2 hours the mixture was poured on to ice,extracted with AcOEt, washed in succession with Na pyrosulphitesolution, 2N NaOH and NaCl solution, dried and evaporated. Mediumpressure chromatography on silica gel (hexane/AcOEt=85/15) followed byrecrystallization from hexane/AcOEt finally yielded 760 mg of ethyl(2E,4E,6E)-7-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoateas colourless crystals of melting point 116°-120° C. (dec.). Moreover,170 mg of the over-oxidized 6,7-epoxy derivative were obtained.

EXAMPLE 16

In analogy to Example 15 there was manufactured:

Ethyl(2E,4E,6E)-7-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoateas pale yellow crystals of m.p. 98°-99° C.

EXAMPLE 17

254 mg of ethyl(2E,4E,6E)-7-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoatewere placed in 2 ml of EtOH/THF=1/1 and treated with 0.5 ml of 3N NaOH.The mixture was stirred overnight, poured on to ice, acidified withconc. HCl, extracted with AcOEt, washed with a small amount of water,dried and evaporated i.v. Crystallization from AcOEt/hexane yielded 139mg of(2E,4E,6E)-7-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoicacid as colourless crystals, m.p. 164°-165° C.

EXAMPLE 18

In analogy to Example 17 there was manufactured:

(2E,4E,6E)-7-(8-Heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoicacid as pale yellow crystals of m.p. 152°-153° C.

EXAMPLE 19

In analogy to Example 15 there was manufactured:

Ethyl(2E,4E,6E)-7-(5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-8-octyl-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoateas colourless crystals of m.p. 88°-890° C.

EXAMPLE 20

In analogy to Example 17 there was manufactured:

(2E,4E,6E)-7-(5,5-Dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-8-octyl-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoicacid as pale yellow crystals of m.p. 104°-105° C.

EXAMPLE 21

In analogy to Example 9 there was manufactured:

Methyl (E)-4- 2-(6-heptyloxy-3,3-dimethyl-1,1-dioxo-2,3-dihydro-benzob!thiophen-5-yl)propenyl!-benzoate as white crystals of m.p. 95°-96° C.

The 6-bromo-3,3-dimethyl-2,3-dihydrobenzo b!thiophene used as thestarting material was synthesized as follows:

17.08 g of 3-bromothiophenol were placed in 60 ml of acetone and treatedat 0° C. with 37.3 g of powdered K₂ CO₃. Then, 10.1 ml of ethylbromoacetate were slowly added dropwise thereto and the mixture was leftto react for 1 hour. Subsequently, the mixture was poured on to ice,extracted with EtOEt, washed with water, dried over Na₂ SO₄ andevaporated. There were thus obtained 24.05 g of product (GC>98%), whichwas processed as follows:

The corresponding Grignard compound was prepared from 5.46 g of Mgshavings and 14.5 ml of MeI in 150 ml of abs. EtOEt under argonaccording to the standard procedure. 22.8 g of the ester prepared above,dissolved in 70 ml of abs. EtOEt, were added dropwise thereto at -10° C.After 1 hour the mixture was poured on to ice/NH₄ Cl, extracted withEtOEt, washed with sat. NaCl solution, dried over Na₂ SO₄ andevaporated. Flash chromatography on silica gel (hexane/AcOEt=85/15) gave11.94 g of tertiary alcohol which was cyclized as follows:

21.7 g of AlCl₃ were placed in 80 ml of CS₂ under argon. 11.94 g of thetertiary alcohol prepared above, dissolved in 10 ml of CS₂, were addeddropwise at 0° C. while stirring. The mixture was heated to reflux for 3hours, cooled, poured cautiously on to ice and extracted with hexane.The organic phase was washed with water, dried over Na₂ SO₄ and thesolvent was removed i.v. Flash chromatography on silica gel (hexane)yielded 9.54 g of a mixture which according to GC contained 36.5% of thedesired 6-bromo-3,3-dimethyl-2,3-dihydro-benzo b!thiophene and 60% ofthe regioisomeric 4-bromo compound. Separation was effected at the nextstage, after conversion into the corresponding phenols, which wascarried out as described under Example 9d).

EXAMPLE 22

In analogy to Example 11 there was manufactured:

(E)-4- 2-(6-Heptyloxy-3,3-dimethyl-1,1-dioxo-2,3-dihydrobenzob!thiophen-5-yl)propenyl!-benzoic acid as white crystals of m.p.151°-152° C.

Example A

Hard gelatine capsules can be produced as follows:

    ______________________________________                                mg/    Ingredients                 capsule    ______________________________________    1. Spray-dried powder containing 75% of compound I                                20    2. Sodium dioctylsulphosuccinate                                0.2    3. Sodium carboxymethylcellulose                                4.8    4. Microcrystalline cellulose                                86.0    5. Talc                     8.0    6. Magnesium stearate       1.0    Total                       120    ______________________________________

The spray-dried powder, which is based on the active ingredient,gelatine and microcrystalline cellulose and which has an averageparticle size of the active ingredient of <1μ (measured by means ofautocorrelation spectroscopy), is moistened with an aqueous solution ofsodium carboxymethylcellulose and sodium dioctylsulphosuccinate andkneaded. The resulting mass is granulated, dried and sieved, and thegranulate obtained is mixed with microcrystalline cellulose, talc andmagnesium stearate. The powder is filled into size 0 capsules.

Example B

Tablets can be produced as follows:

    ______________________________________    Ingredients             mg/tablet    ______________________________________    1. Compound I as a finely milled powder                             20    2. Powd. lactose        100    3. White corn starch     60    4. Povidone K30          8    5. White corn starch    112    6. Talc                  16    7. Magnesium stearate    4    Total                   320    ______________________________________

The finely milled active ingredient is mixed with lactose and a portionof the corn starch. The mixture is moistened with an aqueous solution ofPovidone K30 and kneaded, and the resulting mass is granulated, driedand sieved. The granulate is mixed with the remaining corn starch, talcand magnesium stearate and pressed to tablets of suitable size.

Example C

Soft gelatine capsules can be prepared as follows:

    ______________________________________    Ingredients     mg/capsule    ______________________________________    1. Compound I    5    2. Triglyceride 450    Total           455    ______________________________________

10 g of compound I are dissolved in 90 g of medium-chain triglyceridewhile stirring and under inert gasification and protection from light.The solution is processed as a capsule fill mass to soft gelatinecapsules containing 5 mg of active ingredient.

Example D

A lotion can be produced as follows:

    ______________________________________    Ingredients    ______________________________________    1. Compound I finely milled                          1.0       g    2. Carbopol 934       0.6       g    3. Sodium hydroxide   q.s. ad pH                                    6    4. Ethanol, 94%       50.0      g    5. Demineralized water                          ad 100.0  g    ______________________________________

The active ingredient is incorporated into the 94% ethanol/water mixturewith protection from light. Carbopol 934 is stirred in until gelling iscomplete and the pH value is adjusted with sodium hydroxide.

We claim:
 1. A fused bicyclic compound of the formula: ##STR13## whereinX is --S--, --SO-- or --SO₂ --; R¹ is C₇₋₁₀ -alkyl or C₇₋₁₀ -alkoxy; R²is a residue of the formula ##STR14## and R³ is carboxy orlower-alkoxycarbonyl; or salts of said bicyclic compound when R³ iscarboxy.
 2. The compound of claim 1 wherein X is --SO₂ --.
 3. Thecompound of claim 2 wherein R² is ##STR15## and R³ is as above.
 4. Thecompound of claim 3 wherein said compound is methyl-4-2-(8-octyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoate.5. The compound of claim 3 wherein said compound is methyl-4-2-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoate.6. The compound of claim 3 wherein said compound is methyl-4-2-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoate.7. The compound of claim 3 wherein said compound is 4-2-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoicacid.
 8. The compound of claim 3 wherein said compound is 4-2-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoicacid.
 9. The compound of claim 3 wherein said compound is 4-2-(8-octyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl!-benzoicacid.
 10. The compound of claim 2 wherein R² is ##STR16##
 11. Thecompound of claim 10 wherein said compound is7-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoicacid.
 12. The compound of claim 10 wherein said compoundethyl-7-(5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-8-octyl-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate.13. The compound of claim 10 wherein said compound is7-(5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-8-octyl-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoicacid.
 14. The compound of claim 10 wherein said compound is ethyl-7-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate.15. The compound of claim 10 wherein said compound is ethyl-7-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate.16. The compound of claim 10 wherein said compound is7-(8-hexyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoicacid.